The effect of histamine (HA) on the release of endogenous norepinephrine (NE) from superfused rat hypothalamic and striatal slices was assessed. Measurements were made by high-performance liquid chromatography with electrochemical detection. Superfusion with HA (0.1-80 microM) resulted in a concentration-dependent increase (10-220%) of NE release from hypothalamus but was ineffective in the striatum. The process was Ca++-dependent and was unaffected by blockade of monoamine oxidase. The H2 agonists, dimaprit (50 microM) and impromidine (10 microM), increased NE release from hypothalamic slices 3-fold and 2-fold, respectively. Tiotidine (10 microM), an H2 antagonist, did not alter the spontaneous release of NE but completely abolished the effect of dimaprit. To increase the ability of the tissue to sustain NE release on repeated stimulation, tyrosine was added to the perfusion medium. Under these conditions 10 microM HA produced, in two consecutive stimuli, a 1.9-fold increase. Two consecutive stimuli by 80 microM HA elicited a 3.2- and a 2.9-fold increase. Under the same conditions, 50 microM ranitidine, another H2 antagonist, but not pyrilamine, an H1 antagonist, completely blocked the effect of 10 microM HA. Although NE release was increased in the presence of tyrosine, tyrosine did not increase the tissue levels of NE. These experiments imply that H2 receptor activation increases release of NE from the rat hypothalamus. Since in the hypothalamic slice, noradrenergic nerve endings are cut from their cell bodies, the modulatory event must have occurred at the nerve terminals.